The complement system is an essential part of the body's natural defence mechanism against foreign invasion and is also involved in the inflammatory process. More than 30 proteins in serum and at the cell surface are involved in complement system function and regulation. Recently it has become apparent that, as well as the ˜35 known components of the complement system which may be associated with both beneficial and pathological processes, the complement system itself interacts with at least 85 biological pathways with functions as diverse as angiogenesis, platelet activation, glucose metabolism and spermatogenesis (Mastellos, D., et al., Clin Immunol, 2005. 115(3): p. 225-35).
The complement system is activated by the presence of foreign antigens. Three activation pathways exist: (1) the classical pathway which is activated by IgM and IgG complexes or by recognition of carbohydrates; (2) the alternative pathway which is activated by non-self surfaces (lacking specific regulatory molecules) and by bacterial endotoxins; and (3) the lectin pathway which is activated by binding of manna-binding lectin (MBL) to mannose residues on the surface of a pathogen. The three pathways comprise parallel cascades of events that result in the production of complement activation through the formation of similar C3 and C5 convertases on cell surfaces resulting in the release of acute mediators of inflammation (C3a and C5a) and formation of the membrane attack complex (MAC). The parallel cascades involved in the classical and alternative pathways are shown in FIG. 1.
Complement can be activated inappropriately under certain circumstances leading to undesirable local tissue destruction. Inappropriate complement activation has been shown to play a role in a wide variety of diseases and disorders including acute pancreatitis, Alzheimer's disease, allergic encephalomyelitis, allotransplatation, asthma, adult respiratory distress syndrome, burn injuries, Crohn's disease, glomerulonephritis, haemolytic anaemia, haemodialysis, hereditary angioedema, ischaemia reperfusion injuries, multiple system organ failure, multiple sclerosis, myasthenia gravis, ischemic stroke, myocardial infarction, psoriasis, rheumatoid arthritis, septic shock, systemic lupus erythematosus, stroke, vascular leak syndrome, transplantation rejection and inappropriate immune response in cardiopulmonary bypass operations. Inappropriate activation of the complement system has thus been a target for therapeutic intervention for many years and numerous complement inhibitors targeting different parts of the complement cascade are under development for therapeutic use.
In ischemic stroke and myocardial infarction, the body recognises the dead tissue in the brain or heart as foreign and activates complement so causing further local damage. Similarly in cardiopulmonary bypass operations, the body recognises the plastic surfaces in the machine as foreign, activates complement and can result in vascular damage. In autoimmune diseases, the body may wrongly recognise itself as foreign and activate complement with local tissue damage (e.g. joint destruction in rheumatoid arthritis and muscle weakness in myasthenia gravis).
Myasthenia gravis is a chronic autoimmune disease that results in progressive fatigue, loss of muscle tone and increasing paralysis. These symptoms are caused by inappropriate activation of complement resulting in an immune response directed against the nicotinic acetylcholine receptor (AchR) which leads, in turn, to reduced neuromuscular transmission. Myasthenia gravis may occur in association with other diseases such as a thymic tumor or thyrotoxicosis, as well as with rheumatoid arthritis and lupus erythematosus.
There is currently no cure for myasthenia gravis. The disease is usually treated initially using anticholinesterase agents, such as neostigmine bromide (Prostigmin) and pyridostigmine bromide (Mestinon), which help improve neuromuscular transmission and increase muscle strength. Treatment with anticholinesterase agents is, however, associated with adverse side effects caused from acetylcholine accumulation including gastrointestinal complaints and increased bronchial and oral secretions. In addition, although anticholinesterase agents often provide symptomatic benefit, they do not influence the course of the disease. Patients who do not respond to anticholinerterase agents may also be treated with long-term immunosuppressive drugs such as the cortocosteroid prednisone, or other immunosuppressant drugs such as cyclosporine, azathioprine and cyclophosphamide. These immunosuppressant drugs are, however, associated with serious side effect. Corticosteroids side effects include weight gain, osteoporosis, hypertension and glaucoma. Azathioprine and cyclosporine are associated with liver dysfunction and an increased risk of malignancy. In some cases, thymectomy is recommended as an alternative to drugs but the response is unpredictable and symptoms of the disease may continue for months or years after surgery.
Experimental autoimmune myasthenia gravis (EAMG) may be induced in animal models by immunisation with purified AChR or anti-AChR antibodies and these models are useful in assessing the effect of complement inhibitors on the progression of the disease. The complement inhibitor soluble complement receptor 1 (sCR1) has been shown to delay weight loss and reduce clinical signs of EAMG, suggesting that this molecule may be useful in the treatment for myasthenia gravis (Piddlesden et al, J. Neuroimmunol., 1996, 71: 173-177). However, daily injections of sCR1 were required to achieve these effects and, although sCR1 reduced weight loss, it did not completely prevent it. sCR1 does not therefore completely prevent the symptoms of myasthenia gravis.
Furthermore, sCR1 acts by binding early products of the complement cascade, C3b and C4b. The complement system plays an important and valuable role in defence against pathogens and many of the early by-products of the cascade are important in the recognition and opsonisation of pathogenic organisms. For this reason, therapeutic intervention in the earlier stages of the classical and alternative pathways is considered to carry the risk of increased susceptibility to microbial infection (Roos, A., et al., Immunobiology, 2002, 205(4-5): p. 595-609).
There is thus a great need for agents that improve upon the currently available treatments for myasthenia gravis.